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O riginal Paper
European
Neurology
Hur Neurol 1997:37:186-189
Received: December 11. 1995
Accepted: October 11,1996
Prolongation of QTc Interval in
Patients with Parkinson's Disease
Hisayoshi Oka
Soichiro Mochio
Hironori Sato
Ko Katayama
Internal Medicine (III), Jikei University
School of Medicine. Minato-ku, Tokyo,
Japan
Key W ords
Abstract
QTc interval
Parkinson’s disease
Autonomic dysfunction
Valsalva maneuver
Baroreceptor reflex
QTc intervals were measured in 30 patients with Parkinson’s disease and 30
healthy control subjects. The mean value of QTc intervals in patients with
Parkinson’s disease significantly exceeded that of healthy controls (418 ±
14 ms vs. 403 ± 18 ms). Prolongation of the QTc interval was unrelated to the
administration of levodopa. The mean QTc interval in patients whose Hoehn
and Yahr score was III or more was significantly greater than that of patients
whose score was II or less (424 ± 12 ms vs. 410 ± 12 ms). A significant corre­
lation between the QTc interval and the Valsalva ratio, as well as the over­
shoot, was identified. The QTc interval is closely related to autonomic ner­
vous system dysfunction, including abnormal baroreceptor reflex function, in
patients with Parkinson’s disease.
Autonomic nervous system dysfunction is a common
finding in Parkinson's disease. However, it has been
reported that severe autonomic dysfunction is actually
quite rare in patients with Parkinson’s disease.
QT interval prolongation and shortening on electrocar­
diography are influenced by the autonomic nervous sys­
tem [1, 2], However, the QT interval also changes in
response to alterations in the R-R interval [3, 4], In order
to exclude the influence of the R-R interval on the QT
interval, a corrected QT interval (QTc) calculated from
Bazett’s formula, (QTc = QT s R-R) [5], has been widely
used. This method has the advantage of simple applica­
tion.
It has been reported that the QTc interval is prolonged
in diabetic patients [6-10]. We have also suggested that
QTc prolongation shows a significant correlation with
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cardiac autonomic nervous dysfunction [11]. Therefore,
QTc prolongation may be recognized in patients with Par­
kinson’s disease, which is accompanied by autonomic
nervous system dysfunction.
In this study, we measured the QTc interval in patients
with Parkinson’s disease and investigated its relation to
disease duration and severity as well as other autonomic
function tests affected by Parkinson’s disease. We have
also attempted to clarify the significance of QTc interval
prolongation in Parkinson's disease.
Subjects and M ethods
QTc Interval in Parkinson's Disease
The QTc interval was measured in 30 subjects with Parkinson’s
disease (15 males, 15 females, mean age ± SD 64.3 ± 12.0 years)
and 30 age-matched healthy controls (15 males, 15 females, mean age
± SD 64.3 ± 11.7 years). After the subjects had been lying quietly
Hisayoshi Oka. MD. PhD
Third Dept, of Internal Medicine
Jikei University School of Medicine
3-25-8 Nishi-Shinabashi, Minato-ku
Tokyo 105 (Japan)
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Introduction
Relation to Ollier Autonomic Function Tests
In 23 randomly chosen patients with Parkinson’s disease (mean
age 56.5 years), we examined the Valsalva ratio, overshoot, cold pres­
sor test and changes in blood pressure upon standing. The relation­
ships between these results and the QTc interval were evaluated. The
Valsalva maneuver consisted of blowing into a mouthpiece at a pres­
sure of 40 mm Hg for 15 s. R-R intervals were recorded during and
after the maneuver, and the ratio of the longest R-R interval (ob­
tained shortly after the maneuver) to the shortest R-R interval (ob­
tained during the maneuver) defined the Valsalva ratio. In addition,
systolic blood pressures were obtained during and after the Valsalva
maneuver with a continuous blood pressure monitoring system,
CBM-2000 (Nihon Colin Co. Ltd.. Tokyo, Japan). The Valsalva
overshoot is defined as the difference between the rebound systolicblood pressure following the maneuver and the initial pre-Valsalva
blood pressure. The cold pressor test, in which changes in systolic
blood pressure are measured while the subject has 1 hand in ice water
(4°C). was also performed. Changes in systolic blood pressure before
and after 5 min of standing were measured after the subject had been
lying at rest for more than 20 min. Orthostatic hypotension was
defined as a fall in systolic blood pressure of 30 mm Hg or more upon
standing.
Statistical Methods
The significance of differences was determined by Student’s t
test. A p < 0.05 was considered to indicate a statistically significant
difference. The relationship between QTc interval and various auto­
nomic function tests was evaluated by linear regression analysis.
Analysis of covariance was employed to evaluate the independent
contribution of severity of disease to QTc interval by adjusting the
effect of dosage of levodopa.
QTc Prolongation in Parkinson’s Disease
Valsalva
ratio
Fig. 1. Relationship between QTc interval and Valsalva ratio in
Parkinson’s patients (n = 23, p < 0.05. r = -0.472).
Results
QTc Interval in Parkinson’s Disease
The QTc interval in subjects with Parkinson’s disease
(418 ± 14 ms) was significantly (p < 0.001) greater than
that in healthy controls (403 ± 18 ms).
Relations to the Duration and Severity o f Disease
No significant differences in the QTc intervals were
found between patients whose disease duration was short
(less than 5 years; n = 17.419 ± 14 ms) versus those with
long disease duration (5 or more years; n = 13, 417 ±
15 ms). However, the QTc interval in patients with Par­
kinson’s disease whose Hoehn and Yahr score was III or
more (n = 17, 424 ± 12 ms) significantly (p < 0.05)
exceeded that of those who had a Hoehn and Yahr of II or
less (n = 13, 410 ± 12 ms).
Relation to Autonomic Nervous Dysfunction
There were no significant correlations between the
QTc interval and blood pressure changes either on the
cold pressor test or upon standing. However, as shown in
figures 1 and 2, there were significant correlations be­
tween QTc intervals and the Valsalva ratio, as well as the
Valsalva overshoot.
Relation to Levodopa Administration
There were no significant differences in the QTc inter­
val of Parkinson’s patients taking levodopa versus those
Eur Neurol 1997;37:186-189
187
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for more than 10 min. the QTc interval was measured using an FCP2201 ECG recorder (Fukuda-Denshi Co. Ltd., Tokyo. Japan). The
QTe interval was calculated from Bazett's formula. The R-R interval
was obtained from 10 measurements in the lead yielding the longest
QT interval. The QT interval was measured from the beginning of
the Q-wave to the point at which the T-wave became isoelectric. All
subjects w»ere examined before lunch. Among the subjects showing
no ischemic change on the ECG. those who were found to have elec­
trolyte imbalances, or were on antiarrhythmic or a- and |)-blocker
medications were excluded from this study.
The duration of Parkinson’s disease ranged from 1 to 12 years,
with a mean of 4.4 years. Subjects consisted of 1 patient with Hoehn
and Yahr I. 12 with II. 13 with III and 4 with IV. Hoehn and Yahr
stages were evaluated in the on state. Eight patients were not taking
medications. Eleven patients were being treated with levodopa (100—
300 mg) in combination with carbidopa. The remaining patients
were on levodopa (400-600 mg) in combination with carbidopa.
Patients on other anti-Parkinson’s drugs were excluded from this
study. All patients met the UK Parkinson's Disease Society Brain
Bank clinical diagnostic criteria for idiopathic Parkinson’s disease
[ 12]. Patients with multiple system atrophy, such as Shy-Dragcr syn­
drome and olivopontocerebellar atrophy, were also excluded accord­
ing to the criteria of Quinn [ 13).
The healthy controls were chosen from among subjects screened
in an annual health check-up. None had hypertension or abnormal
ECG, were on medication, or had other medically significant find­
ings. Informed consent was obtained from all study participants.
40-1
30-
—
10 -*---- "
1
------ 1-------------1-------------1------------- 1------------- -------------1
380
400
420
440
460
480
Q T c interval
ms
F ig . 2 . Relationship between QTc interval and Valsalva over­
shoot in Parkinson's patients (n = 23, p < 0.05, r = -0.445).
not taking levodopa (418 ± 15 ms) or between those on
different dosages of levodopa (100-300 mg: 420 ± 8 ms;
400-600 mg: 416 ± 11 ms). After adjusting for the dosage
of levodopa by analysis of covariance, Hoehn and Yahr
score was still a significant contributor to QTc interval
(p = 0.041).
D isc u ssio n
It has been reported that the QT interval is shortened
by stimulating sympathetic function [14] and prolonged
by reducing sympathetic function [1], Although these
studies point to a predominantly sympathetic influence
[15-17], parasympathetic nervous function has also been
implicated as a modulator of QT duration [2]. However,
since the QT interval may be changed by the preceding
R-R interval, it is important to exclude the influence of
the R-R interval when using the QT interval as a parame­
ter of autonomic nervous function [3-5, 18]. Correction
of the QT interval (QTc interval) by Bazett’s formula is
the most widely utilized means of evaluating QT prolon­
gation [5], However, the QTc interval may still be in­
fluenced by the R-R interval in the setting of tachycardia
or bradycardia [3]. Parasympathetic tone predominates
188
F.ur Neurol 1997;37:186-189
Oka/Mochio/Sato/Katayama
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Valsalva
o ve rsh oo t
m m Hg
over sympathetic tone in the sinus node at rest [19]. The
R-R interval is shortened when parasympathetic nervous
system function is decreased. The QTc interval is pro­
longed since it is corrected by dividing by , R-R. The
QTc interval appears to be prolonged not only by sympa­
thetic but also by parasympathetic nervous system dys­
function.
QTc prolongation has been reported in diabetic pa­
tients. We have suggested that the QTc interval correlates
with the Valsalva ratio as well as the overshoot, but not
with blood pressure elevation on the cold pressor test, in
diabetic patients. We have also observed QTc prolonga­
tion to be associated with the results of spectral analysis of
the R-R interval and to show a significant correlation with
cardiac autonomic but not vasomotor nervous function.
In this study, QTc intervals correlated significantly
with both the Valsalva ratio as well as the Valsalva over­
shoot in patients with Parkinson's disease. The Valsalva
ratio reflects sympathetic in addition to parasympathetic
function, because reflex bradycardia occurs in response to
vagal activity following a blood pressure overshoot. The
Valsalva overshoot reflects sympathetic nervous system
function because sympathetic activity, which manifests as
tachycardia and peripheral vasoconstriction, stimulates
baroreceptors when the arterial pulse pressure drops.
Therefore, the QTc interval is considered to be closely
related to parasympathetic and sympathetic nervous sys­
tem function, including the baroreceptor reflex, in Parkin­
son’s disease.
We also found that prolongation of the QTc interval
was related to disease severity, as assessed by the Hoehn
and Yahr score, but not to disease duration. Orskov et al.
[20] reported that sympathetic nervous dysfunction corre­
lated with disease duration in Parkinson’s patients. How­
ever, their patients were not receiving levodopa treat­
ment. Eight patients in our study were not being treated
with levodopa, 11 cases were on low doses (100-300 mg),
and 11 cases were on high doses (400-600 mg) of levodo­
pa. It is known that levodopa-treated patients with Par­
kinson’s disease have symptoms of sympathetic nervous
dysfunction, including orthostatic hypotension [21, 22],
Therefore, prolongation of the QTc interval, an indicator
of autonomic dysfunction including sympathetic nervous
dysfunction, must be taken into consideration as a possi­
ble effect of levodopa treatment. However, no significant
differences in the QTc interval were recognized between
subjects taking versus those not taking levodopa, or be­
tween subjects with different dosages. These findings
indicate that QTc prolongation is unrelated to the admin­
istration of levodopa. It is well known that the dorsal
nucleus of vagus is involved in Parkinson’s disease. Dis­
turbance of the dorsal nucleus of vagus induces cardiac
parasympathetic dysfunction. As mentioned above, the
QTc interval is prolonged in the setting of parasympathet­
ic dysfunction. This QTc prolongation indicates cardiac
autonomic dysfunction, specifically the parasympathetic
dysfunction associated with Parkinson’s disease. The QTc
interval may serve as a simple indicator of cardiac auto­
nomic dysfunction in Parkinson’s disease.
References
QTc Prolongation in Parkinson's Disease
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